Two-Year Results of a First-In-Human Study in Patients Surgically Implanted With a Bioprosthetic Venous Valve, the VenoValve in Patients With Severe Chronic Venous Insufficiency.

OBJECTIVE: Two-year follow-up results from a first-in-human study of patients implanted with the VenoValve are evaluated for supporting the long-term clinical safety and performance of the device. BACKGROUND: Chronic Venous Insufficiency (CVI) involves improper functioning of lower limb vein valves and inability of these valves to move blood back towards the heart. CVI symptoms include swelling, varicose veins, pain, and leg ulcers. Currently, there is no cure for this condition and treatment options are limited. This study provides 2-year outcomes for 8 patients who were implanted with the bioprosthetic VenoValve for treating severe CVI with deep venous reflux measured at the mid-popliteal vein. The 6-month and 1-year results were previously published. METHODS: Eleven patients with C5 & C6 CVI were implanted with VenoValve into the midthigh femoral vein and followed for 2 years. Assessed clinical outcomes include device-related adverse events, reflux time, disease severity, and pain scores. RESULTS: All 11 implant procedures were successful. Two-year follow-up data was obtained for 8 subjects: 1 patient died of non-device related causes, 1 was lost to follow-up, and 1 refused to follow-up due to the COVID-19 pandemic. No device-related adverse events occurred between the first and second years of follow-up. Reported 2-year clinical performance outcomes included significant decreases in mean reflux times of the mid-popliteal vein (61%), and significant improvements in mean scores for disease severity rVCSS (56%) and VAS pain (87%). CONCLUSIONS: Results from this study support long-term safety and effectiveness of the VenoValve for improving CVI severity by reducing reflux and thereby venous pressures in the lower extremities. With limited treatments for valvular incompetence involved in severe, deep venous CVI, the device may be considered as a novel therapy. A pivotal trial in the United States is currently being conducted to assess the device in a larger number of patients.

Mutations in EPHB4 cause human venous valve aplasia.

Venous valve (VV) failure causes chronic venous insufficiency, but the molecular regulation of valve development is poorly understood. A primary lymphatic anomaly, caused by mutations in the receptor tyrosine kinase EPHB4, was recently described, with these patients also presenting with venous insufficiency. Whether the venous anomalies are the result of an effect on VVs is not known. VV formation requires complex "organization" of valve-forming endothelial cells, including their reorientation perpendicular to the direction of blood flow. Using quantitative ultrasound, we identified substantial VV aplasia and deep venous reflux in patients with mutations in EPHB4. We used a GFP reporter in mice to study expression of its ligand, ephrinB2, and analyzed developmental phenotypes after conditional deletion of floxed Ephb4 and Efnb2 alleles. EphB4 and ephrinB2 expression patterns were dynamically regulated around organizing valve-forming cells. Efnb2 deletion disrupted the normal endothelial expression patterns of the gap junction proteins connexin37 and connexin43 (both required for normal valve development) around reorientating valve-forming cells and produced deficient valve-forming cell elongation, reorientation, polarity, and proliferation. Ephb4 was also required for valve-forming cell organization and subsequent growth of the valve leaflets. These results uncover a potentially novel cause of primary human VV aplasia.

Saphenous vein valve assessment utilizing upright CT to potentially improve graft assessment for bypass surgery.

Saphenous veins (SVs) are frequently employed as bypass grafts. The SV graft failure is predominantly seen at the valve site. Avoiding valves during vein harvest would help reduce graft failure. We endeavored to detect SV valves, tributaries, and vessel size employing upright computed tomography (CT) for the raw cadaver venous samples and in healthy volunteers. Five cadaver legs were scanned. Anatomical analysis showed 3.0 (IQR: 2.0-3.0) valves and 13.50 (IQR: 10.00-16.25) tributaries. The upright CT completely detected, compared to 2.0 (IQR: 1.5-2.5, p = 0.06) valves and 9.5 (IQR: 7.5-13.0, p = 0.13) tributaries by supine CT. From a total of 190 volunteers, 138 (men:75, women:63) were included. The number of valves from the SF junction to 35 cm were significantly higher in upright CT than in supine CT bilaterally [upright vs. supine, Right: 4 (IQR: 3-5) vs. 2 (IQR:1-2), p < 0.0001, Left: 4 (IQR: 3-5) vs. 2 (IQR: 1-2), p < 0.0001]. The number of tributaries and vessel areas per leg were also higher for upright compared with supine CT. Upright CT enables non-invasive detection of SV valves, tributaries, and vessel size. Although not tested here, it is expected that upright CT may potentially improve graft assessment for bypass surgery.

Persistent Right Venous Valve: Insights From Multimodality Imaging.

Anatomic variants in the right atrium are under-recognized and under-reported phenomena in cardiac imaging. In the fetus, right atrium serves as a conduit for oxygenated blood to be delivered to the left heart bypassing the right ventricle and the nonfunctional lungs. The anatomy in the fetal right atrium is designed for such purposeful circulation. The right and left venous valves are prominent structures in the fetal heart that direct inferior vena caval flow towards the foramen ovale. These anatomic structures typically regress and the foramen ovale closes after birth. However, the venous valves can persist leading to a range of anatomic, physiological, and pathological consequences in the adult. We describe various presentations of persistent venous valves, focusing on the right venous valve in this illustrated multimodality imaging article.

Functional ultrasound imaging of the venous valve of the great saphenous vein in the area around the crosse using the novel vector flow technique.

PURPOSE: The aim of our pilot study is to consider if the new flow presentation of the vector flow (V-flow) allows an assessment of the valve morphology of the crosses with respect to an insufficiency. MATERIAL AND METHODS: We performed a total of 50 investigations in which we documented a complete valve closure at the so called "crosse" at the valve of the large saphenous vein, a delayed valve closure or an incomplete valve closure with consecutive insufficiency at the crosse. The valve function of the crosse is crucial for the development of varicosis. For our study we recorded age and gender of the patients. One patient in the study was suffering from Covid19. For the examinations we used a 3-9 MHz probe and a high-end ultrasound device. The examination was performed in a lying position and under quiet conditions. Before examination we practiced inhalation and exhalation as well as "pressing" or coughing with the patients, which resulted in a physiological closure of the venous valves. To rule out thrombosis, we carried out compression sonography on the legs. During the examination we documented the B-scan, the Color-Coded Duplex Sonography, the HR-flow and the V-flow for 3 seconds at the estuary of the crosses and incorporated these parameters into our measurements. Via V-flow, vectors can be imaged by representing the flow of erythrocytes and visually indicate a possible insufficiency due to delayed or incomplete valve closure. RESULTS: 31 of 50 patients (age 19-81years) showed a complete valve closure of the crosses, three of them suffered from thrombosis. In eight of the 50 study participants (age 45-79 years) a delayed valve closure could be diagnosed by V-flow within 1-2 seconds. None of them had a thrombosis, but six of them suffered from cancer. In eleven patients we derived an incomplete valve closure with insufficiency (age 51-88 years). With reflux it took >2 seconds to close the valve. The patient with Covid19 also showed an incomplete valve closure with insufficiency. At the same time this patient showed a Covid19-associated deep vein thrombosis. Eight additional patients also had a thrombosis. Six of them suffered from cancer. Overall, the results were best visualized by V-Flow. CONCLUSION: The crosse as a significant venous structure can be well investigated by V-flow with respect to hemodynamic changes and a resulted reflux. Also associated changes close to the valve can be visualized well.

Using two-dimensional ultrasound imaging to examine venous pressure.

Ultrasound imaging is being used increasingly to aid in the teaching of human physiology and anatomy. Here we describe how its use can be integrated into the teaching of concepts surrounding venous circulation, specifically 1) venous valves and the muscle pump, 2) the effects of hydrostatic pressure on venous pressure, and 3) central venous pressure. The imaging procedures described are relatively simple but add a dimension that helps deliver the teaching points clearly and is enjoyable for students. They also aid in the link of basic physiology to clinical aspects of venous circulatory physiology.

Morphology of the Vieussens valve and its imaging in cardiac multislice computed tomography.

INTRODUCTION: To deliver accurate morphological descriptions of the Vieussens valve (VV) and to investigate whether this structure could be visualized using standard contrast-enhanced electrocardiogram-gated multislice computed tomography (MSCT). METHODS: A total of 145 human autopsied hearts and 114 cardiac MSCT scans were examined. RESULTS: The VV was observed in both study groups, however, the detection rate was significantly worse in the MSCT examination (18.4% in MSCT vs 62.1% in cadavers, P < .0001). The VV height was larger in MSCT patients (2.8 ± 1.2 vs 5.4 ± 1.7 mm; P < .0001). No significant difference was found in the measured distance between the VV and the coronary sinus ostium between the two separate subgroups (27.3 ± 9.5 vs 24.4 ± 5.8 mm; P = .18). In autopsied material the most frequent valve location was the anterior wall of the coronary sinus (43.3%); the same was observed in MSCT scans (71.4%). CONCLUSION: The VV is a common heart structure, present in over 60% of humans, located mainly on the anterior and superior circuit of the coronary sinus, with relatively high morphological variability. Large VVs, which pose a significant obstacle in catheterization procedures, may be visualized using standard-protocol contrast-enhanced cardiac MSCT.

[Functional assessment of primary lesion of the great saphenous vein when deciding upon stripping]. / Funktsional'naia otsenka pervichnogo porazheniia bol'shoi podkozhnoi veny pri reshenii voprosa o stripinge.

The purpose of the study was to examine a possibility of functional assessment of the great saphenous vein (GSV) with the help of a day orthostatic loading test for prognosis of restoration of the function of the GSV afterremoving its varicose tributaries in patients with primary varicose veins. Our prospective study included a total of sixty-five 29-to-53-year-old patients (15 men and 50 women, mean age - 36.7 years). The total number of the lower limb examined amounted to 87. All patients underwent ultrasonographic examination (duplex scanning) prior to operation, 1 and 12 months thereafter. The study was carried out using a day orthostatic loading test consisting in duplex scanning performed twice during 24 hours: in the evening after 18:00 hours and in the morning before 10:00 hours after a good night's rest. It was demonstrated that the day orthostatic loading test characterized the degree of preservation of the muscular-tonic properties of the GSV, making it possible to predict reversibility of reflux along it after removing the varicose tributaries, hence it may be used as a criterion for individualization of the choice of the scope of surgical intervention. A high orthostatic gradient prior to operation suggests preservation of the potential of the muscular-tonic function of the GSV; its decrease after surgery demonstrates reduction of the volemic loading on the GSV.

A pilot study of venous duplex ultrasound parameters in healthy children.

OBJECTIVE: The spectrum of chronic venous disease (CVD) in adults is well documented, whereas there is a paucity of data published commenting on pediatric CVD. We previously identified that there is often venous reflux present in cases of pediatric lower extremity edema despite an alternative confirmed diagnosis. To further assess the clinical significance of this venous reflux, this study aimed to elicit venous parameters in healthy pediatric controls. METHODS: Healthy pediatric volunteers aged 5 to 17 years were recruited for venous reflux study. A comprehensive venous reflux study was performed with the patient standing. Vein diameter, patterns of valvular reflux, and accessory venous anatomy were examined in the deep and superficial venous systems. RESULTS: Eighteen children including 10 boys and 8 girls were studied. Five volunteers were aged 5 to 8 years, six volunteers were aged 9 to 12 years, and seven volunteers were aged 13 to 17 years. Great saphenous vein (GSV) diameter at the saphenofemoral junction significantly increased with age. Deep vein valve closure time (VCT) did not differ significantly between groups, whereas GSV VCT was significantly higher in the 9- to 12-year age group. Incidental venous insufficiency was identified in 60% of children aged 5 to 8 years (n = 3), 50% of children aged 9 to 12 years (n = 3), and 57% of children aged 13 to 17 years (n = 4). All superficial venous reflux was confined to the GSV; there were no cases of isolated deep venous reflux. Reflux was identified at multiple GSV stations in 60% of children. There was no significant difference in incompetent GSV VCT in comparing children with and without deep venous reflux. Accessory superficial veins were identified in 20% of children aged 5 to 8 years (n = 1), 50% of children aged 9 to 12 years (n = 3), and 43% of children aged 13 to 17 years (n = 3). The presence of an accessory saphenous vein was not associated with deep venous reflux in any patient, and only 29% of those with accessory saphenous venous anatomy had evidence of superficial venous (GSV) reflux. CONCLUSIONS: The GSV continues to grow in diameter through the teenage years. Incidental valvular incompetence and GSV reflux are common. The presence of accessory saphenous veins is similarly common and not associated with venous reflux. The clinical significance and natural history of this incidental venous reflux remain unclear. Future research should determine whether these changes seen in the pediatric age group lead to CVD during later years of life.

A case report of cough headache with transient elevation of intracranial pressure and bilateral internal jugular vein valve incompetence: A primary or secondary headache?

Background Primary cough headache (PCH) is precipitated by coughing or the Valsalva manoeuver (VM), and its underlying pathophysiology remains unclear. Case report We report a case of recurrent cough headaches precipitated by VM with transient increase of intracranial pressure (ICP) diagnosed by measuring left sigmoid sinus pressure. Bilateral internal jugular vein valve incompetence (IJVVI) was also diagnosed by Doppler ultrasonography during a VM. Indomethacin was administered for over four months, and the headache had completely disappeared at the four-month follow-up. Conclusions Cough headache might be associated with a transient increase of ICP induced by IJVVI, which might partially explain the pathophysiology of VM-induced headache. Detecting the internal jugular vein during a VM might be used as diagnostic procedure for patients who have PCH during resting and VM. If it is necessary, monitoring the ICP could be considered.

Aging of the venous valves as a new risk factor for venous thrombosis in the elderly: the BATAVIA study.

Essentials Risk of venous thrombosis (VT) related to valve thickness and valvular reflux in unknown. Venous valves and reflux were measured by ultrasonography in cases and controls aged 70+. Risk of VT was associated with increased valve thickness and valvular reflux >1second. Thickening of valves is a generic process: there was no difference between right and left legs. SUMMARY: Background Increasing age is the strongest risk factor for venous thrombosis (VT). Increasing age has been related to a thickening of the venous valves and a decreased valvular function. The association between valve thickness and the risk of VT is not known. Objectives To assess the association between increased valve thickness and valve closure time (VCT) and the risk of VT. Methods Analyses were performed in the BATAVIA study, including 70 cases aged 70 + with a first VT and 96 controls. We performed an ultrasound examination of the valves in the popliteal veins. The valves were imaged with a 9 MHz linear probe using B-mode ultrasonography. VCT was measured as an indicator for valve function using an automatic inflatable cuff. To estimate the risk of VT, valve thickness was dichotomized at the 90th percentile as measured in controls and VCT was dichotomized at 1 s. Results Mean valve thickness of controls was similar in the left (0.36 mm, 95% CI 0.34-0.37) and right (0.36 mm, 95% CI 0.35-0.38) leg. In 45 cases a valve was observed in the contralateral leg with a mean valve thickness of 0.39 mm (95% CI 0.36-0.42). Cases had an increased valve thickness compared with controls: mean difference 0.028 mm (95%CI 0.001-0.055). Valve thickness > 90th percentile increased the risk of VT 2.9-fold. Mean VCT in controls was 0.38 s, in contralateral leg of cases 0.58 s. VCT > 1 s increased the risk of VT 2.8-fold (95% CI 0.8-10.4). Conclusions Risk of VT was associated with increased valve thickness and valvular reflux of > 1 s.

[Method of preventive ultrasound diagnosis of venous thrombosis]. / Metod preventivnoi ul'trazvukovoi diagnostiki venoznykh trombozov.

AIM: The purpose of the study was to work out a method of preventive diagnosis of venous thromboses by means of ultrasonographic duplex scanning (USDS). PATIENTS AND METHODS: A total of 306 people were examined. Of these, 146 patients presented with acute venous thrombosis, 108 subjects suffered from varicose veins, and 52 were apparently healthy people composing the control group. All those enrolled into the study were examined by means of USDS, with the D-dimer level determined. RESULTS: The obtained findings made it possible to discover and duly describe an ultrasonographic phenomenon of the presence of echo-positive inclusions in the zone of valvular sinuses, which was called the phenomenon of spontaneous echo contrast (SEC). This was followed by working out a classification of this phenomenon, describing two degrees thereof. Degree 1 SEC reflects the fact that the area of valvular sinuses is the most thrombogenic zone. Degree 2 SEC is characterised as a pathological, being simultaneously pre-thrombotic, condition and may serve as one of the earliest predictors of the development of venous thrombosis. A close correlation was established between the degree 2 SEC phenomenon, the presence of venous thrombosis and the values of the D-dimer level (r=0.89, p<0.01). CONCLUSION: Ultrasonographic examination of valvular sinuses is a simple, readily available and reproducible method of screening and may thus be used for preventive diagnosis of acute venous thromboses. The findings of this study make it possible to form risk groups by the development of deep vein thrombosis, as well as to initiate timely measures on prevention of the pathology concerned.

High Resolution M-mode Evaluation of Jugular Vein Valves in Patients with Neurological and Neurosensory Disorders.

BACKGROUND: High prevalence of valve absence was found in the internal jugular vein (IJV) of healthy volunteers by means of M-mode high-resolution Echo Colour Doppler (ECD). However, the prevalence of valve in neurovascular disorders linked to Chronic Cerebrospinal Venous Insufficiency (CCSVI) is still unknown. METHODS: A cohort of 83 Healthy Controls (HC), 71 Multiple Sclerosis (MS), 99 Inner Ear Disorders (IED) underwent ECD investigation of the IJV valve, including M-mode evaluation and related hemodynamics. The primary outcome measure was characterization of valve presence, morphology and motility, whereas the secondary outcome was the rate of flow alteration. RESULTS: Bilateral valve presence was found in 38% of HC, 58% of MS and 25% of IED, whereas, bilateral valve absence was recorded in 16% of HC, 10% of MS and 31% of IED (p<0.003). Bicuspid morphology was more prevalent in HC 56%, while monocusp was more prevalent in patients: 75% MS and 57% IED (p<0.0001). The main finding was the presence of mobile valve leaflets in 98% of HC, contrarily fixed valve leaflets were recorded in 82% of MS and in 41% of IED, p< 0.0001. Finally, by stratifying the entire cohort according to the presence of mobile and not mobile valve leaflets, normal monodirectional and phasic flow were commonly found in the mobile leaflets subgroup, p<0.0001. CONCLUSION: In patients with miscellaneous neurological disorders, a significant higher rate of defective valves was found with respect to HC. The latter condition is strongly associated to brain outflow abnormalities described in CCSVI condition.

Determining the origin of superficial venous reflux in the groin with duplex ultrasound and implications for varicose vein surgery.

OBJECTIVE: The purpose of this paper was to describe patterns of superficial reflux in the groin with respect to the terminal valve (TV), which is located at the saphenous opening to the common femoral vein, the great saphenous vein, and its tributary veins. METHODS: This study included 2019 legs with chronic venous insufficiency that received endoluminal varicose vein treatment because of varicosities with insufficiency of the saphenofemoral junction (SFJ). In a preoperative duplex ultrasound investigation of the superficial vein system, reflux after provocation in the SFJ, great saphenous vein, cranial veins (superficial external pudendal vein, superficial epigastric vein, superficial circumflex iliac vein), and anterior and posterior accessory saphenous veins was recorded and classified on the basis of the origin of reflux. RESULTS: In 1348 legs (66.8%), the reflux had its origin exclusively in the common femoral vein. In 170 legs (8.4%), the reflux had its origin in the common femoral and cranial veins. In 430 legs (21.3%), the insufficiency was due to saphenocranial reflux only. In 71 legs (3.5%), the origin of reflux could not be determined. CONCLUSIONS: Reflux in the SFJ does not involve the TV in 24.8% of the legs, implying that routine high ligation and ablation close to the TV might be overtreatment in these patients.

Differential Diagnosis and Clinical Implications of Remnants of the Right Valve of the Sinus Venosus.

Anatomic variants of the remnants of the right valve of the sinus venosus in adults are common and usually observed on cardiac imaging studies. Because the anatomy and function of these vestiges are not well known, errors may occur in the differential diagnosis and treatment of patients with unclear images in the right atrium. Clinical implications may arise from (1) differential diagnosis with some diseases, especially when the remnants act as sites of attachment for masses; (2) the need for invasive treatment if the anatomic variant displays obstructive behavior; (3) the association between remnants and patent foramen ovale; and (4) secondary complications related to these structures in invasive procedures. Thus, the aim of this review is to provide cardiologists and radiologists specializing in cardiac imaging techniques with the basic anatomic information and clinical implications required to understand morphologic variants of right sinus venosus valve vestiges in adults.